Evaluating the clinical implications for ACKR1/DARC associated neutropenia

摘要： 白细胞(WBC)计数和中性粒细胞计数是最常用的医学检测方法。白细胞 在骨髓抑制治疗的环境中密切监测计数和绝对中性粒细胞计数(ANC)， 而中性粒细胞减少通常是给药化疗时的剂量限制毒性。白细胞计数的升高也是 用于帮助诊断和感染以及对急性细菌感染患者进行风险分层。因此， WBC和中性粒细胞计数的准确解释在医学的许多分支中都是至关重要的。WBC和 中性粒细胞计数因种族和民族而有很大差异。非洲裔美国人，具有非洲血统的拉丁裔和 一些中东人群的WBC和ANC较低。我们之前已经绘制了基因图谱 这种差异背后的变种。该变异体映射到Duffy抗原受体的启动子区域 趋化因子(DARC/ACKR1)基因座与红细胞表面DARC抗原表达缺失的关系 血细胞。导致表达丧失的等位基因(Fya-/b-或Fy-)是西非的主要等位基因， 但在非洲和中东以外的地区很少见。携带FY/-基因的个体有WBC和ANC，即&gt；1 标准差低于其他基因型的个体。尽管有十多年的知识关于 这种效果，在将其纳入临床护理方面进展甚微。因此，患有这种疾病的患者 在美国，以非裔美国人为主的基因可能会接受较低剂量的骨髓抑制 而且可能更有可能降低化疗的相对剂量强度，这可能导致 结果上的差异。由于WBC和ANC被用来诊断和作出预后推断 患者感染时，其护理环境中的严重感染可能会受到影响。因此，大型研究与 结果需要帮助指导临床医生如何治疗这些患者。我们建议利用大型 与电子健康记录绑定的生物库，用于确定接受骨髓抑制治疗的患者的结果 并确定如何在感染环境中使用WBC和ANC。(1)我们会研究 慢性骨髓抑制治疗患者的基因分型结果。我们将决定是否财年-/- 基因型别与骨髓抑制治疗中性粒细胞减少症的高发生率有关，以及这是否会导致 减少剂量。我们将检查FY-/-ON患者感染并发症的风险 骨髓抑制疗法。(2)我们将根据基因分型检查患者的化疗结果。 我们将确定基因型是否与化疗的相对剂量强度有关，以及这是否 与这些患者总体存活率的差异有关。我们将确定感染性并发症 在接受化疗的患者中与基因有关。(3)我们将研究WBC和中性粒细胞如何 在急性感染的环境中，淋巴细胞计数比率不同，以及这如何影响诊断和预后 使用这些参数。我们的项目将帮助临床医生优化骨髓抑制治疗和诊断 在大量携带该基因的个体中感染。

Abstract: White blood cell (WBC) counts and neutrophil counts are among the most commonly used medical tests. WBC counts and absolute neutrophil counts (ANC) are monitored closely in the setting of myelosuppressive therapy, and neutropenia is often the dose limiting toxicity when dosing chemotherapy. An elevated WBC count is also used in helping to diagnose and infection and risk stratifying patients with acute bacterial infections. Therefore, accurate interpretation of the WBC and neutrophil count is crucial in many branches of medicine. WBC and neutrophil counts vary substantially by race and ethnicity. African Americans, Latinos with African ancestry and some Middle Eastern populations have lower WBC and lower ANC. We have previously mapped the genetic variant underlying this difference. The variant maps to the promoter region of the Duffy Antigen Receptor Chemokine (DARC/ACKR1) locus and results in lack of expression of the DARC antigen on the surface of red blood cells. The allele which leads to loss of expression (Fya-/b- or Fy-) is the predominant allele in West Africa, but rare outside of Africa and the Middle East. Individuals with Fy-/- genotype have WBC and ANC that is > 1 standard deviation lower than individuals with the other genotype. Despite over a decade of knowledge about this effect, there has been little progress on incorporating this into clinical care. As a result, patients with this genotype who are predominantly African American in the U.S. may receive lower doses of myelosuppressive therapies and may be more likely to have reduced relative dose intensity of chemotherapy which may lead to disparities in outcomes. Since WBC and ANC are used to diagnose and make prognostic inferences among patients with infection, their care in the setting of severe infections may suffer. Therefore, large studies with outcomes are needed to help guide clinicians on how to treat these patients. We propose to leverage large biobanks tied to electronic health records to determine outcomes of patients on myelosuppressive therapies with this genotype and to determine how to use WBC and ANC in the setting of infection. (1) We will examine outcomes of patients on chronic myelosuppressive therapies by genotype. We will determine whether Fy-/- genotype is associated with high incidence of neutropenia on myelosuppressive therapies and whether this leads to dose reductions. We will examine the risk of infectious complications among patients with Fy-/- on myelosuppressive therapies. (2) We will examine outcomes of patients on chemotherapy according to genotype. We will determine if genotype is associated with relative dose intensity of chemotherapy and whether this is associated with differences in overall survival among these patients. We will determine if infectious complications are associated with genotype among patients on chemotherapy. (3) We will examine how WBC and neutrophil to lymphocyte count ratios vary in the setting of acute infections and how this affects diagnostic and prognostic use of these parameters. Our project will help clinicians optimize myelosuppressive therapy and diagnosis of infection among the large number of individuals with this genotype.